Gastric cancer is one of the major cancers that cause death. Gastric cancers are histopathologically classified into differentiated gastric cancers and undifferentiated gastric cancers, where the latter includes poorly differentiated adenocarcinoma, signet-ring cell carcinoma, mucinous carcinoma and the like.
In the case of undifferentiated gastric cancer, cancer cells are likely to diffuse and also likely to develop fibrosis that leads to scirrhous gastric cancer. Undifferentiated gastric cancer is commonly observed in young people, and is known to cause invasive proliferation and metastasis, indicating a poor prognosis(1).
FGFR2 (also referred to as “K-sam”) is amplified in diffuse-type gastric cancer, namely, undifferentiated gastric cancer and is known to be involved in malignant alteration of cancer(1,2). FGFR2 gene is reported to be amplified in 33% of patients with undifferentiated gastric cancer(2), and FGFR2 is reported to be positive in about 50% of patients with undifferentiated gastric cancer(1). FGFR2 gene induces transformation of NIH3T3 cell, and the transformed cell is reported to show tumorigenicity in nude mice(3). Furthermore, FGFR2 truncated at C-terminal is reported to have a strong transformation activity and predominantly expressed in undifferentiated gastric cancer cell line(1,3)). For example, FGFR2 having residues downstream from tyrosine at 769 deleted is reported to have a high transformation activity(3).
It is also reported that FGFR2 gene is amplified in poorly differentiated gastric cancer, particularly scirrhous gastric cancer, while FGFR2 protein having C-terminal (including tyrosine residues 780, 784 and 813) deleted is specifically expressed in scirrhous gastric cancer(4). Amplification of activated FGFR2 is reported to cause tumor growth in scirrhous gastric cancer(4).
Examples of conventionally-used chemotherapeutic substances for gastric cancer include 5-fluorouracil analogs and paclitaxel analogs. None of them, however, have satisfactory anti-tumor effect and thus there has been a strong need for development of a novel anti-tumor agent.
A FGFR2 inhibitor, diphenylamine derivative, is recently reported to dose-dependently suppress cell growth of a human scirrhous gastric cell line and show anti-tumor effect on a subcutaneous transplanted (xenograft) model of human scirrhous gastric cell line(5).
A FGFR2 inhibitor, 4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]quinazoline, is suggested to be effective on gastric cancer overexpressing K-sam(6).
Accordingly, a FGFR2 inhibitor is suggested to show antiproliferative action and anti-tumor effect on undifferentiated gastric cancers, preferably poorly differentiated adenocarcinoma, signet-ring cell carcinoma, mucinous carcinoma and scirrhous gastric cancer.
Here, a compound represented by General Formula (I) is known as an antiangiogenic substance(7-9). However, there is no report that the compound represented by General Formula (I) has a FGFR2 inhibitory activity.
Moreover, there has been no report as to whether a combination of these compounds will bring any effect.